The citation and/or discussion of cited references in this section and throughout the specification is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the present invention.
Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defense against an invading pathogen. Interleukin (IL)-17 producing T helper cells (TH17) are a recently identified subset, separate from the T helper type 1 (TH1) and T helper type 2 (TH2) subsets1. The TH17 response is a pro-inflammatory T cell response that is associated with the release of IL-17 and IL-23 cytokines. It has been closely associated with immunity in response to TLR-activated microbial infections and has been reported in a variety of autoimmune conditions including inflammatory bowel disease, colitis, systemic sclerosis, psoriasis, rheumatoid arthritis, diabetes, and cystic fibrosis. Studies have shown that inhibitory antibodies to IL-17 or mice deficient in IL-17 responses are able to suppress or prevent the TH17 response in disease models for gastrointestinal immunity, experimental autoimmune encephalitis (EAE), and rheumatoid arthritis.
Generation of TH17 responses is also thought to be favored at mucosal sites for protective immunity. Importantly, mucosal sites represent a primary target for delivery of vaccines, because most infections affect or start from a mucosal surface. Moreover, often in these infections, application of a vaccine directly to the mucosal surface is required to induce an effective, protective immune response [Holmgren, J. and C. Czerkinsky, Nat Med (2005) 11(4 Suppl):S45-53], since induction of peripheral immune responses by parenteral immunization does not result in significant mucosal immunity [Kiyono, H., et al. Reg Immunol, (1992) 4(2):54-62; McGhee, J. R., et al., Vaccine, (1992) 10(2):75-88].
The effort that has been focused thus far on inducing effective immune responses in mucosal tissues has met with considerable challenge, since most protein antigens (Ags) are rather weak immunogens when given via the mucosal route. The coadministration of mucosal adjuvants, such as cholera toxin (CT), has been shown to effectively support Ag-specific mucosal immune responses, however, the inherent toxicity of cholera toxin is a major hindrance to its use in humans. Thus, the development of other, effective and reliable mucosal adjuvants, that preferably induce TH17 responses, is of central importance for new generation vaccines [McGhee, J. R., et al. Vaccine (1992) 10(2)75-88]. However, it is important to recognize that tight regulation of these TH17 responses must also be achieved, since TH17 responses are also associated with driving a number of autoimmune diseases. Thus, it is critical that the factors that govern differentiation of TH17 cells in vivo be better understood, so that Th17 responses may be carefully regulated.